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Activation of PPARα and PPARγ induce expression of the hepatic LDL receptor
Author(s) -
Huang Zhiping,
He Wei,
Zhou Xiaoye,
Nicholson Andrew C,
Gotto Antonio M,
Hajjar David P
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1137
Subject(s) - ldl receptor , troglitazone , medicine , endocrinology , fenofibrate , peroxisome proliferator activated receptor , chemistry , cholesterol , receptor , biology , lipoprotein
The LDLR plays a key role in cholesterol homeostasis. LDLR mutations cause familial hypercholesterolemia and premature coronary heart disease. Genetic deletion of the LDLR induces atherosclerosis in mice fed a high‐fat diet. LDLR expression is predominantly regulated by SREBP2. PPARα and PPARγ, ligand‐activated transcription factors regulating energy homeostasis and lipid metabolism, are anti‐atherogenic in human and mouse models of atherosclerosis. We investigated the effects of activation of PPARα and PPARγ on LDLR expression in mouse hepatocytes and liver. Treatment of HepG2 cells with fenofibrate, a PPARα ligand, or troglitazone, a PPARγ ligand, induced expression of LDLR mRNA and protein, increased LDL binding and restored LDLR expression inhibited by LDL and 25‐hydroxycholesterol. Activation of PPARα and PPARγ increased the maturation of SREBP2 and was dependent on phosphorylation of Akt. In vivo, a high‐fat diet suppressed LDLR expression in mouse liver and elevated plasma LDL‐cholesterol; however, fenofibrate and troglitazone restored the high‐fat diet‐inhibited hepatic LDLR expression and reduced plasma LDL cholesterol. Taken together, our data suggest PPARα and PPARγ ligands activate Akt phosphorylation leading to increased hepatic LDLR expression and reduced plasma LDL cholesterol levels. Supported by NHLBI PO1‐ HL072942 /The Silbermann and Abercrombie Foundations.